One of the primary aims of surgical anesthesia is to render the patients analgesic, thereby permitting the performance of surgical procedures without painful discomfort. The search continues for the "ideal" analgesic agent because conventionally available anesthetics and opioid analgesics possess various untoward side effects. The understanding of their modes and sites of action on the nervous system is essential for this search. Our long term objectives of the research project are to clarify the analgesic mechanisms of various agents. One of the new and major developments during the past decade for the control of pain during perioperative periods has been spinally administered opioid analgesia. The specific aim of this proposed project is to clarify its mechanism of action. Spinally administered opioids come in contact with the cerebrospinal fluid, the spinal cord and primary afferent nerves. Therefore, the proposed study is aimed at four categories: 1) Studies of opioid action upon primary afferent nerves by examining: a) opioid effects on individual components of compound action potentials (A-beta, A-delta and C), and b) opioid effects on electrical discharges of single nonciceptive afferent peripheral nerve fibers; 2) Studies of opioid action upon the spinal cord neurons of the marginal layer oof Waldeyer as well as low-threshold and proprioceptive neurons; 3) Studies on the penetration process of the spinally administered opioids utilizing radiolabeled ligand; and 4) Studies on the mechanisms of respiratory depression following spinal administration of opioids. As in any newly developed technique, various complications have been reported since the inception of spinal opioid analgesia in man in 1979. One of the most serious and potentially fatal complications is respiratory depression. The last category (4) will address this problem by examining nerve impulse activity recorded from efferent fibers in the lower intercostal, upper intercostal, phrenic, vagus nerves, and medullary respiratory neurons. The clarification of the mechanisms of spinally administered opioid analgesia will provide an increase in the therapeutic value of this newly developed method of pain control and will decrease its potentially fatal complications, e.g. respiratory depression.